It is estimated that 10% of the population is affected by sensorineural or "nerve" deafness that usually arises from sensory hair cell loss or damage. Sensory deficits resulting from hair cell loss have been considered irreversible because the production of human hair cells ceases before birth. In contrast, hair cells are produced postembryonically in the ears of cold-blooded and some warm-blooded vertebrates (birds); in some, thousands of new hair cells can be replaced through trauma-evoked regenerative proliferation. Evidence has shown that supporting cells proliferate and that new hair bundles can appear in vivo in the balance organs of mammals after antibiotic poisoning of hair cells. These findings suggest that hair cell regeneration may be induced in the ears of humans. In order to develop clinical therapies that will bring about hair cell regeneration in the human ear, we must identify the cellular and molecular signals responsible for triggering the regenerative proliferation of inner ear supporting cells after hair cell death, and determine how these cells go on to form hair cells. The goal of the proposed research is to identify factors that regulate regenerative replacement of hair cells in the ears of warm-blooded vertebrates during postembryonic life. This application proposes to investigate the following hypotheses: 1) Endogenous growth factors may negatively regulate inner-ear stem/progenitor cell proliferation, and 2) Robust regenerative proliferation of stem/progenitor cells in mature inner-ear SE may require a simultaneous release from negative regulation coupled with mitogenic signaling by the EGF and/or IGF pathways. These hypotheses will be tested using a combination of techniques, including expression profiling, cell localization, viral gene transfer, cell culture, and quantitative RT-PCR techniques. [unreadable] [unreadable] [unreadable]